{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:33:15Z","timestamp":1791304395604,"version":"4.3.1"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T00:00:00Z","timestamp":1633392000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T00:00:00Z","timestamp":1633392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100001146","name":"Greenwall Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001146","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Eleanor and Miles Shore Award"},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["TL1TR001880"],"award-info":[{"award-number":["TL1TR001880"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007929","name":"Institute for Translational Medicine and Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007929","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Nevoid basal cell carcinoma syndrome (NBCCS) is a tumor predisposition condition, the cardinal features of which emerge in adolescence or adulthood. Using statistical optimization, this study proposes NBCCS criteria with improved sensitivity in children less than 18\u00a0years of age. Earlier detection may lead to improved surveillance and prevention of sequelae. A survey eliciting medical history was completed by, or on behalf of, individuals with NBCCS. Based on these findings, criteria for suspicion of NBCCS in children were suggested using information from a Bernoulli na\u00efve Bayes classifier relying on the human phenotype ontology. The sensitivity and specificity of the existing and proposed diagnostic criteria were also assessed. Participants (n\u2009=\u200948) reported their first signs of NBCCS appeared at a median age of 8\u00a0months, but by our retrospective analysis, they did not fulfill the current diagnostic criteria until a median age of 7\u00a0years. This study delineates the early-onset features of NBCCS and proposes criteria that should prompt consideration of NBCCS. Additionally, we demonstrate a method for quantitatively assessing the utility of diagnostic criteria for genetic disorders.<\/jats:p>","DOI":"10.1038\/s41598-021-98752-9","type":"journal-article","created":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T13:52:53Z","timestamp":1633441973000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Proposed criteria for nevoid basal cell carcinoma syndrome in children assessed using statistical optimization"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0867-722X","authenticated-orcid":false,"given":"Nina B.","family":"Gold","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian M.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Sheppard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hann","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"98752_CR1","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1002\/ajmg.a.33139","volume":"152","author":"DG Evans","year":"2010","unstructured":"Evans, D. G. et al. Birth incidence and prevalence of tumor-prone syndromes: Estimates from a UK family genetic register service. Am. J. Med. Genet. Part A 152, 327\u2013332 (2010).","journal-title":"Am. J. Med. Genet. Part A"},{"key":"98752_CR2","doi-asserted-by":"publisher","first-page":"2091","DOI":"10.1002\/ajmg.a.34128","volume":"155","author":"AF Bree","year":"2011","unstructured":"Bree, A. F. & Shah, M. R. Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). Am. J. Med. Genet. Part A 155, 2091\u20132097 (2011).","journal-title":"Am. J. Med. Genet. Part A"},{"key":"98752_CR3","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1097\/01.GIM.0000144188.15902.C4","volume":"6","author":"RJ Gorlin","year":"2004","unstructured":"Gorlin, R. J. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet. Med. 6, 530\u2013539 (2004).","journal-title":"Genet. Med."},{"key":"98752_CR4","doi-asserted-by":"publisher","first-page":"4155","DOI":"10.1200\/JCO.2014.58.2569","volume":"32","author":"MJ Smith","year":"2015","unstructured":"Smith, M. J. et al. Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J. Clin. Oncol. 32, 4155\u20134161 (2015).","journal-title":"J. Clin. Oncol."},{"key":"98752_CR5","doi-asserted-by":"publisher","first-page":"103842","DOI":"10.1016\/j.ejmg.2020.103842","volume":"63","author":"K Casano","year":"2020","unstructured":"Casano, K. et al. Gorlin-like phenotype in a patient with a PTCH2 variant of uncertain significance. Eur. J. Med. Genet. 63, 103842 (2020).","journal-title":"Eur. J. Med. Genet."},{"key":"98752_CR6","doi-asserted-by":"crossref","unstructured":"Evans, D. G. et al. First evidence of genotype\u2013phenotype correlations in Gorlin syndrome. J. Med. Genet. 54, 530 LP\u2013536 (2017).","DOI":"10.1136\/jmedgenet-2017-104669"},{"key":"98752_CR7","doi-asserted-by":"crossref","unstructured":"Smith, M. J. et al. Germline mutations in SUFU cause gorlin syndrome\u2014associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J. Clin. Oncol. 32 (2014).","DOI":"10.1200\/JCO.2014.58.2569"},{"key":"98752_CR8","doi-asserted-by":"publisher","first-page":"e62","DOI":"10.1158\/1078-0432.CCR-17-0595","volume":"23","author":"WD Foulkes","year":"2017","unstructured":"Foulkes, W. D. et al. Cancer surveillance in Gorlin syndrome and rhabdoid tumor predisposition syndrome. Clin. Cancer Res. 23, e62\u2013e67 (2017).","journal-title":"Clin. Cancer Res."},{"key":"98752_CR9","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1111\/imj.13429","volume":"47","author":"AJ Huq","year":"2017","unstructured":"Huq, A. J. et al. Cohort study of Gorlin syndrome with emphasis on standardised phenotyping and quality of life assessment. Intern. Med. J. 47, 664\u2013673 (2017).","journal-title":"Intern. Med. J."},{"key":"98752_CR10","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1001\/jamadermatol.2016.4347","volume":"153","author":"DC Solis","year":"2016","unstructured":"Solis, D. C., Kwon, G. P. & Ransohoff, K. J. Risk factors for basal cell carcinoma among patients with basal cell nevus syndrome: Development of a basal cell nevus syndrome patient registry. JAMA Dermatol. 153, 189\u2013192 (2016).","journal-title":"JAMA Dermatol."},{"key":"98752_CR11","doi-asserted-by":"crossref","unstructured":"Leme, D. E. S. et al. Assessment of clinical scoring systems for the diagnosis of Williams-Beuren syndrome. funpecrp.com.br Genet. Mol. Res. Genet. Mol. Res. 12, 3407\u20133411 (2013).","DOI":"10.4238\/2013.September.4.7"},{"key":"98752_CR12","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1136\/jmedgenet-2018-105625","volume":"56","author":"MP Adam","year":"2019","unstructured":"Adam, M. P. et al. Kabuki syndrome: International consensus diagnostic criteria. J. Med. Genet. 56, 89\u201395 (2019).","journal-title":"J. Med. Genet."},{"key":"98752_CR13","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1002\/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P","volume":"91","author":"CL Shovlin","year":"2000","unstructured":"Shovlin, C. L. et al. Diagnostic criteria for Hereditary Hemorrhagic Telangiectasia (Rendu- Osler-Weber Syndrome). Am. J. Med. Genet. 91, 66\u201367 (2000).","journal-title":"Am. J. Med. Genet."},{"key":"98752_CR14","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1136\/jmg.31.1.20","volume":"31","author":"TR Cole","year":"2008","unstructured":"Cole, T. R. & Hughes, H. E. Sotos syndrome: A study of the diagnostic criteria and natural history. J. Med. Genet. 31, 20\u201332 (2008).","journal-title":"J. Med. Genet."},{"key":"98752_CR15","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1136\/jmg.30.6.460","volume":"30","author":"DGR Evans","year":"1993","unstructured":"Evans, D. G. R. et al. Complications of the naevoid basal cell carcinoma syndrome: Results of a population based study. J. Med. Genet. 30, 460\u2013464 (1993).","journal-title":"J. Med. Genet."},{"key":"98752_CR16","doi-asserted-by":"crossref","unstructured":"Kimonis, V. et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am. J. Med. Genet. Part A 69 (1998).","DOI":"10.1002\/(SICI)1096-8628(19970331)69:3<299::AID-AJMG16>3.0.CO;2-M"},{"key":"98752_CR17","unstructured":"Alpaydin, E. Introduction to Machine Learning. (MIT Press, 2010)."},{"key":"98752_CR18","doi-asserted-by":"publisher","first-page":"2564","DOI":"10.1093\/bioinformatics\/btt446","volume":"29","author":"S Sheppard","year":"2013","unstructured":"Sheppard, S., Lawson, N. D. & Zhu, L. J. Accurate identification of polyadenylation sites from 30 end deep sequencing using a naive Bayes classifier. Bioinformatics 29, 2564\u20132571 (2013).","journal-title":"Bioinformatics"},{"key":"98752_CR19","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s10462-007-9052-3","volume":"26","author":"SB Kotsiantis","year":"2006","unstructured":"Kotsiantis, S. B., Zaharakis, I. D. & Pintelas, P. E. Machine learning: A review of classification and combining techniques. Artif. Intell. Rev. 26, 159\u2013190 (2006).","journal-title":"Artif. Intell. Rev."},{"key":"98752_CR20","doi-asserted-by":"publisher","first-page":"2180","DOI":"10.1056\/NEJMoa1113538","volume":"366","author":"JY Tang","year":"2012","unstructured":"Tang, J. Y. et al. Inhibiting the Hedgehog pathway in patients with the basal-cell nevus syndrome. N. Engl. J. Med. 366, 2180\u20132188 (2012).","journal-title":"N. Engl. J. Med."},{"key":"98752_CR21","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ccr.2012.11.017","volume":"23","author":"J Kim","year":"2013","unstructured":"Kim, J. et al. Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell 23, 23\u201334 (2013).","journal-title":"Cancer Cell"},{"key":"98752_CR22","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.ejca.2017.08.022","volume":"86","author":"N Basset-S\u00e9guin","year":"2017","unstructured":"Basset-S\u00e9guin, N. et al. Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial. Eur. J. Cancer 86, 334\u2013348 (2017).","journal-title":"Eur. J. Cancer"},{"key":"98752_CR23","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1177\/1203475415612481","volume":"20","author":"S Baker","year":"2016","unstructured":"Baker, S., Joseph, K. & Tai, P. Radiotherapy in Gorlin syndrome: Can it be safe and effective in adult patients?. J. Cutan. Med. Surg. 20, 159\u2013162 (2016).","journal-title":"J. Cutan. Med. Surg."},{"key":"98752_CR24","first-page":"1","volume":"8","author":"IK Ali","year":"2016","unstructured":"Ali, I. K. et al. Nevoid basal cell carcinoma syndrome\u2014Clinical and radiological findings of three cases. Cureus 8, 1\u20137 (2016).","journal-title":"Cureus"},{"key":"98752_CR25","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1002\/ajmg.a.34421","volume":"158 A","author":"M Endo","year":"2012","unstructured":"Endo, M. et al. Nationwide survey of nevoid basal cell carcinoma syndrome in Japan revealing the low frequency of basal cell carcinoma. Am. J. Med. Genet. Part A 158 A, 351\u2013357 (2012).","journal-title":"Am. J. Med. Genet. Part A"},{"key":"98752_CR26","unstructured":"Evans, D. G. R. & Farndon, P. A. Nevoid Basal Cell Carcinoma Syndrome. Genereviews (2018). https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1151\/. Accessed: 12th August 2021."},{"key":"98752_CR27","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1111\/j.1399-0004.2010.01527.x","volume":"79","author":"K Nagao","year":"2011","unstructured":"Nagao, K. et al. Entire PTCH1 deletion is a common event in point mutation-negative cases with nevoid basal cell carcinoma syndrome in Japan. Clin. Genet. 79, 196\u2013198 (2011).","journal-title":"Clin. Genet."},{"key":"98752_CR28","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1002\/ajmg.a.34216","volume":"158 A","author":"EA Muller","year":"2012","unstructured":"Muller, E. A. et al. Microdeletion 9q22.3 syndrome includes metopic craniosynostosis, hydrocephalus, macrosomia, and developmental delay. Am. J. Med. Genet. Part A 158 A, 391\u2013399 (2012).","journal-title":"Am. J. Med. Genet. Part A"},{"key":"98752_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01242-6","author":"K Manickam","year":"2021","unstructured":"Manickam, K. et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. https:\/\/doi.org\/10.1038\/s41436-021-01242-6 (2021).","journal-title":"Genet. Med."},{"key":"98752_CR30","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.ejmg.2005.01.029","volume":"48","author":"JHM Merks","year":"2005","unstructured":"Merks, J. H. M. et al. Prevalence of RIB anomalies in normal Caucasian children and childhood cancer patients. Eur. J. Med. Genet. 48, 113\u2013129 (2005).","journal-title":"Eur. J. Med. Genet."},{"key":"98752_CR31","unstructured":"Gorlin syndrome alliance. (2019)."},{"key":"98752_CR32","doi-asserted-by":"publisher","first-page":"D1018","DOI":"10.1093\/nar\/gky1105","volume":"47","author":"S K\u00f6hler","year":"2019","unstructured":"K\u00f6hler, S. et al. Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources. Nucl. Acids Res. 47, D1018\u2013D1027 (2019).","journal-title":"Nucl. Acids Res."},{"key":"98752_CR33","doi-asserted-by":"publisher","unstructured":"You, B., Liu, X. R., Li, N. & Yan, Y. S. Using information content to evaluate semantic similarity on HowNet. In Proceedings of the 2012 8th International Conference on Computing Intelligence Security CIS 2012 142\u2013145 (2012). https:\/\/doi.org\/10.1109\/CIS.2012.39.","DOI":"10.1109\/CIS.2012.39"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-98752-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-98752-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-98752-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T16:16:13Z","timestamp":1670084173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-98752-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,5]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["98752"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-98752-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,5]]},"assertion":[{"value":"30 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19791"}}